The main objective of this proposal is to test the hypothesis that hyperinsulinemia, comparable to that found in obese hypertensives, any cause chronic hypertension via alterations in renal function. Our studies will focus mainly on the possibility that the hyperinsulinemia initiates hypertension by increasing renal tubular sodium reabsorption, similar to the effect of mineralocorticoids. Our approach will employ animal experimentation, studies in humans, and a theoretical analysis of the effects of insulin on renal function and arterial pressure. The animal experiments are designed to determine whether there is a cause and effect relationship between chronic hyperinsulinemia in dogs with normal kidneys and with various degrees of functional renal reserve, caused by reduced renal mass or increased sodium intake. Studies are also designed to evaluate the importance of changes in activity of the renin-angiotensin system (RAS), aldosterone, the sympathetic nervous system, and atrial natriuretic factor (ANF) in modulating insulin-sodium-blood pressure interrelationships. The relative importance of the direct intrarenal and extrarenal actions of insulin in causing chronic hypertension will also be quantitated. And finally, these studies will evaluate the intrarenal mechanisms, including changes in renal hemodynamics and tubular reabsorption, by which insulin influences renal excretion chronically and the role of extrarenal mechanisms, such as the RAS, aldosterone, the sympathetic nervous system, and ANF in modulating insulin's renal actions. All of these studies will be conducted in chronically instrumented conscious dogs using techniques recently developed in our laboratory that allow us to accurately estimate changes in renal function and systemic hemodynamics for along periods of time. The clinical studies are designed primarily to determine whether insulin resistance, which occurs in peripheral tissues of obese hypertensives, also occurs in the renal tubule. In these experiments, the effects of insulin on renal sodium reabsorption will be evaluated in normotensive and hypertensive non-obese and obese individuals. A systems analysis of the interrelationships between insulin, body fluid homeostasis, and arterial pressure regulation will be developed. The experiments will provide much of the quantitative data needed to develop this analysis and the mathematical analysis will, in turn, be important in evaluating the validity of our hypotheses and in suggesting new areas for experimentation.
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